Recently, we found that a new malaria vaccine, R21/Matrix-M, had over 75% efficacy against clinical malaria with seasonal administration in a phase 2b trial in Burkina Faso. Here, we report on safety and efficacy of the vaccine in a phase 3 trial enrolling over 4800 children across four countries followed for up to 18 months at seasonal sites and 12 months at standard sites. We did a double-blind, randomised, phase 3 trial of the R21/Matrix-M malaria vaccine across five sites in four African countries with differing malaria transmission intensities and seasonality. Children (aged 5–36 months) were enrolled and randomly assigned (2:1) to receive 5 μg R21 plus 50 μg Matrix-M or a control vaccine (licensed rabies vaccine [Abhayrab]). Participants, their families, investigators, laboratory teams, and the local study team were masked to treatment. Vaccines were administered as three doses, 4 weeks apart, with a booster administered 12 months after the third dose. Half of the children were recruited at two sites with seasonal malaria transmission and the remainder at standard sites with perennial malaria transmission using age-based immunisation. The primary objective was protective efficacy of R21/Matrix-M from 14 days after third vaccination to 12 months after completion of the primary series at seasonal and standard sites separately as co-primary endpoints. Vaccine efficacy against multiple malaria episodes and severe malaria, as well as safety and immunogenicity, were also assessed. This trial is registered on , , and is ongoing. From April 26, 2021, to Jan 12, 2022, 5477 children consented to be screened, of whom 1705 were randomly assigned to control vaccine and 3434 to R21/Matrix-M; 4878 participants received the first dose of vaccine. 3103 participants in the R21/Matrix-M group and 1541 participants in the control group were included in the modified per-protocol analysis (2412 [51·9%] male and 2232 [48·1%] female). R21/Matrix-M vaccine was well tolerated, with injection site pain (301 [18·6%] of 1615 participants) and fever (754 [46·7%] of 1615 participants) as the most frequent adverse events. Number of adverse events of special interest and serious adverse events did not significantly differ between the vaccine groups. There were no treatment-related deaths. 12-month vaccine efficacy was 75% (95% CI 71–79; p<0·0001) at the seasonal sites and 68% (61–74; p<0·0001) at the standard sites for time to first clinical malaria episode. Similarly, vaccine efficacy against multiple clinical malaria episodes was 75% (71–78; p<0·0001) at the seasonal sites and 67% (59–73; p<0·0001) at standard sites. A modest reduction in vaccine efficacy was observed over the first 12 months of follow-up, of similar size at seasonal and standard sites. A rate reduction of 868 (95% CI 762–974) cases per 1000 children-years at seasonal sites and 296 (231–362) at standard sites occurred over 12 months. Vaccine-induced antibodies against the conserved central Asn-Ala-Asn-Pro (NANP) repeat sequence of circumsporozoite protein correlated with vaccine efficacy. Higher NANP-specific antibody titres were observed in the 5–17 month age group compared with 18–36 month age group, and the younger age group had the highest 12-month vaccine efficacy on time to first clinical malaria episode at seasonal (79% [95% CI 73–84]; p<0·001) and standard (75% [65–83]; p<0·001) sites. R21/Matrix-M was well tolerated and offered high efficacy against clinical malaria in African children. This low-cost, high-efficacy vaccine is already licensed by several African countries, and recently received a WHO policy recommendation and prequalification, offering large-scale supply to help reduce the great burden of malaria in sub-Saharan Africa. The Serum Institute of India, the Wellcome Trust, the UK National Institute for Health Research Oxford Biomedical Research Centre, and Open Philanthropy.

中文翻译：

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候选疟疾疫苗 R21/Matrix-M 在非洲儿童中的安全性和有效性：多中心、双盲、随机、3 期试验

最近，我们发现，在布基纳法索进行的 2b 期试验中，一种新型疟疾疫苗 R21/Matrix-M 通过季节性给药对临床疟疾有超过 75% 的功效。在这里，我们报告了一项 3 期试验中疫苗的安全性和有效性，该试验在四个国家招募了 4800 多名儿童，在季节性地点进行了长达 18 个月的试验，在标准地点进行了长达 12 个月的试验。我们在疟疾传播强度和季节性不同的四个非洲国家的五个地点进行了 R21/Matrix-M 疟疾疫苗的双盲、随机、3 期试验。儿童（5-36 个月大）被纳入并随机分配 (2:1) 接受 5 μg R21 加 50 μg Matrix-M 或对照疫苗（获得许可的狂犬病疫苗 [Abhayrab]）。参与者、他们的家人、研究人员、实验室团队和当地研究团队均未接受治疗。疫苗分三剂接种，间隔 4 周，第三剂后 12 个月注射加强剂。一半的儿童是在两个季节性疟疾传播地点招募的，其余儿童是在常年疟疾传播的标准地点招募的，使用基于年龄的免疫接种。主要目标是 R21/Matrix-M 从第三次疫苗接种后 14 天到完成主要系列后 12 个月的保护功效，在季节性和标准地点分别作为共同主要终点。还评估了疫苗针对多次疟疾发作和严重疟疾的功效以及安全性和免疫原性。该试验已于 、 、 注册，并且正在进行中。从2021年4月26日至2022年1月12日，5477名儿童同意接受筛查，其中1705名儿童被随机分配至对照疫苗，3434名儿童被随机分配至R21/Matrix-M； 4878 名参与者接受了第一剂疫苗。修改后的符合方案分析中包括 R21/Matrix-M 组的 3103 名参与者和对照组的 1541 名参与者（2412 名 [51·9%] 男性和 2232 名 [48·1%] 女性）。 R21/Matrix-M 疫苗耐受性良好，最常见的不良事件是注射部位疼痛（1615 名参与者中的 301 名[18·6%]）和发烧（1615 名参与者中的 754 名[46·7%]）。疫苗组之间特别关注的不良事件和严重不良事件的数量没有显着差异。没有出现与治疗相关的死亡。对于首次出现临床疟疾的时间，季节性地点的 12 个月疫苗效力为 75% (95% CI 71–79；p<0·0001)，标准地点的 12 个月疫苗效力为 68% (61–74；p<0·0001)插曲。同样，针对多次临床疟疾发作的疫苗功效在季节性地点为 75% (71–78; p<0·0001)，在标准地点为 67% (59–73; p<0·0001)。在随访的前 12 个月中，观察到疫苗效力略有下降，季节性和标准地点的下降幅度相似。 12 个月内，季节性场所每 1000 名儿童年发病率减少 868 例（95% CI 762-974），标准场所每 1000 儿童年发病率减少 296 例（95% CI 762-974）例。疫苗诱导的针对环子孢子蛋白保守的中央 Asn-Ala-Asn-Pro (NANP) 重复序列的抗体与疫苗功效相关。与 18-36 个月龄组相比，5-17 个月龄组观察到更高的 NANP 特异性抗体滴度，并且较年轻的年龄组在季节性首次临床疟疾发作的时间上具有最高的 12 个月疫苗效力（79% [95% CI 73–84]；p<0·001）和标准（75% [65–83]；p<0·001）位点。 R21/Matrix-M 具有良好的耐受性，并且对非洲儿童的临床疟疾具有高效能。这种低成本、高效的疫苗已获得多个非洲国家的许可，最近还获得了世卫组织的政策建议和资格预审，可大规模供应，帮助减轻撒哈拉以南非洲地区疟疾的巨大负担。印度血清研究所、威康信托基金会、英国国家健康研究所牛津生物医学研究中心和开放慈善事业。